The role of viral and cellular miRNAs in B-cell lymphomagenesis

病毒和细胞 miRNA 在 B 细胞淋巴瘤发生中的作用

基本信息

批准号：
8634961
负责人：
Rebecca L Skalsky
金额：
$ 10万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634961
关键词：
AIDS-Related Diffuse Large B-cell Lymphoma Acquired Immunodeficiency Syndrome Acute Address Adult Advisory Committees Apoptosis Apoptotic Automobile Driving Award B Cell Proliferation B lymphoid malignancy B-Cell Activation B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes Binding Bioinformatics Biological Biological Assay Biological Models Biology Cancer Model Cell Survival Cells Clinical Critiques DNA Tumor Viruses Data Development Epithelial Epithelial Cells Epstein-Barr Virus Infections Event Gene Expression Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Goals Growth Hodgkin Disease Homologous Gene Human Human Herpesvirus 4 Immunoprecipitation In Vitro Individual Infection Infectious Mononucleosis LMP1 Laboratories Lead Learning Libraries Life Life Cycle Stages Link Luciferases Lymphoma Lymphomagenesis Lymphoproliferative Disorders Malignant Neoplasms Malignant lymphoid neoplasm Mediating Mentors Messenger RNA Methodology MicroRNAs Modeling Molecular Oncogenic Outcome Pathogenesis Pathway interactions Patients Phase Play Population Porifera Process Regulation Reporter Resources Ribonucleosides Role Sequence Homology Signal Pathway Signal Transduction Staging TNFRSF5 gene Techniques Time Training Viral Viral Pathogenesis Viral Proteins Virus Virus Diseases Western Blotting Writing cell transformation cellular targeting computerized tools crosslink deep sequencing in vivo infected B cell inhibitor/antagonist insight large cell Diffuse non-Hodgkin&apos s lymphoma latent infection latent persistent infection lymphoblastoid cell line meetings member multidisciplinary new therapeutic target programs public health relevance research study tumorigenesis uncontrolled B lymphocyte proliferation viral RNA virology

项目摘要

Project Summary At least one in six human cancers is linked to viral infection. A portion of these can be attributed to Epstein-Barr virus (EBV), a ubiquitous DNA tumor virus associated with cancers such as Burkitt's, Hodgkin's, and diffuse large B cell lymphomas. During infection, EBV expresses viral microRNAs (miRNAs), and recent studies have demonstrated an important role for the EBV miRNAs as well as the cellular oncogenic miRNAs upregulated by EBV infection in the B cell transformation process. Furthermore, several EBV miRNAs share sequence homology with cellular miRNAs that are dysregulated in cancers and potentially, these viral miRNAs can tie into and alter existing miRNA-regulated networks. The miRNA targets involved in transformation are not yet defined, and thus, systemically identifying the genes regulated by miRNAs in EBV-infected cells is essential to understanding their contributions to viral oncogenesis and their roles during the EBV life cycle. Experiments outlined here combine state-of-the-art techniques from the multidisciplinary fields of miRNA biology, virology, and bioinformatics to comprehensively interrogate the miRNA targetome and examine the transcriptional landscape of EBV-infected B cells in order to extract critical genes and pathways influenced by viral and cellular miRNAs. These studies will be carried out using an EBV-driven in vitro B cell transformation model in addition to patient-derived EBV+ B cell tumors. To successfully carry out my studies, I require new training in both EBV biology and bioinformatics, and have accordingly assembled a scientific advisory committee to guide me in establishing and/or further developing several of the essential methodologies. The K99/R00 award will provide me both resources and time for new training during the mentored phase in order to learn fundamental de novo infection techniques and generate additional data and computational tools to be used in my own laboratory during the independent phase. By integrating the miRNA targetome data, transcriptome data, and phenotypic data generated through these experiments, I hope to elucidate the mechanisms by which miRNAs, particularly EBV miRNAs, contribute to persistent viral infection and the development of lymphoma. Finally, since EBV expresses not only viral miRNAs but further alters expression of oncogenic cellular miRNAs that have been linked to many cancers not associated with viral infection, these studies will potentially provide important information that can be extended to other cancer models and provide insight into the overall mechanisms governing miRNA-mediated gene regulation in cancers.

项目概要至少六分之一的人类癌症与病毒感染有关。其中一部分可以归因于 Epstein-Barr 病毒 (EBV) 是一种普遍存在的 DNA 肿瘤病毒，与伯基特氏病、霍奇金氏病、和弥漫性大 B 细胞淋巴瘤。在感染过程中，EBV 表达病毒 microRNA (miRNA)，最近研究表明 EBV miRNA 以及细胞致癌 miRNA 具有重要作用 B 细胞转化过程中 EBV 感染上调。此外，一些 EBV miRNA 共享与癌症中失调的细胞 miRNA 具有序列同源性，并且这些病毒 miRNA 可能可以结合并改变现有的 miRNA 调控网络。参与转化的 miRNA 靶点是尚未定义，因此，系统地鉴定 EBV 感染细胞中受 miRNA 调控的基因是对于了解它们对病毒肿瘤发生的贡献及其在 EBV 生命周期中的作用至关重要。这里概述的实验结合了 miRNA 多学科领域的最先进技术生物学、病毒学和生物信息学全面探究 miRNA 目标组并检查 EBV 感染的 B 细胞的转录景观，以提取受 EBV 影响的关键基因和通路病毒和细胞 miRNA。这些研究将使用 EBV 驱动的体外 B 细胞转化进行除了患者来源的 EBV+ B 细胞肿瘤外，还建立了模型。为了成功地完成我的学业，我需要新的 EBV 生物学和生物信息学方面的培训，并相应地编制了科学咨询委员会指导我建立和/或进一步发展一些基本方法。这 K99/R00 奖项将为我在指导阶段提供新培训的资源和时间，以便学习基本的从头感染技术并生成额外的数据和计算工具在独立阶段在我自己的实验室使用。通过整合 miRNA 目标组数据，通过这些实验产生的转录组数据和表型数据，我希望能够阐明 miRNA（尤其是 EBV miRNA）导致持续病毒感染的机制以及淋巴瘤的发展。最后，由于 EBV 不仅表达病毒 miRNA，还进一步改变致癌细胞的表达 miRNA 与许多与病毒感染无关的癌症有关，这些研究可能会提供可扩展到其他癌症模型的重要信息，并提供对整体癌症模型的洞察癌症中 miRNA 介导的基因调控机制。